Germicide



Patented Jan. 11, 1927f UNITED STATES JOHN WOOLMAN CHUBCHHAN, OF N EW YORK, N. Y:, ASSIGNOB TO NATIONAL ANILINE A 1,614,281 PATENT OFFICE.

& CHEMICAL COMPANY, INC., 01' NEW YORK, N. Y., A CORPORATION 01 NEW'YOBK.

OERMICIDE.

No Drawing.

This invention relates to compositions having antiseptic qualities and is particularly directed to improvements in ermi-v cides having especialutility for their actericidal and bacteriostatic properties, and which may serve as valuable therapeutic agents.

The new compositions of the present invention are made up of substances of o posite selective bactericidal properties w ich together supplement the action of each other,

. such that the composition is bactericidal for all or practically all organisms. The new compositions are made by compounding a substance, such as a triphenylmethane dye,

having normal selective bactericidal power, with a substance, such as acridine dye, having reverse selective bactericidal power, whereby the resulting composition is of practically universal bactericidal power, and is not subject to the limitations of the component ingredients of the composition.

The new compositions of the present invention are composed of ingredients which not only have selective bactericidal or bacteriostatic properties, but which have properties that supplement and reenforce the properties of each other, so that the selective shortcomings of one substance or ingredient are fortified by the selective potencies of the other. ,One or more of the ingredients of the composition has normal selective bactericidal power, while one or moreof the ingredients has the reverse selective bactericidal power.

It has heretofore been observed that certain substances, and particularly certain dyestuffs, exhibit selective bactericidal or bacteriostatic properties which run substantially parallel with the Gram-reaction. The Gram-reaction is a staining method for classifying bacteria; and bacteria are said to be Gramositive if they stain by this .method and ram-negative if they do not. Most pathogenic cocci are Gram-positive while most pathogenic bacilli, except the spore-bearing ones, are Gram-negative. It has been observed for example that certain basic triphenylmethane dyes save a selective action toward living bacteria and that this selective bactericidal action is such that when Gram-positive organisms are subjected thereto the organisms are killed (bactericidal' action) or inhibited (bacteriostatic action), while Gram-negative organisms are 1923. Serial No. 851,434.

in general resistant or unaffected. This selective germicidal or bactericidal action'on Gram-positive bacteria, but not on Gram negative bacteria, ,1 have designated as I n'ormal. Thisnormal selective action has been applied by bacteriologists to the isolation of pure cultures from mixtures, and in the elimination of spurious presumptive tests in potable water and in m1lk for the colon baclllus. It has also proven of definite value in the treatment of infected joints and in the selective sterilization of infected wound surfaces and serous cavities. It has also been observed. that certain other substances exhibit the reverse or opposite bactericidal or bacteriostatic selectivity in that they kill or inhibit Gram-negative organisms and have little or no effect on the Gram-positive ones. This action I have designated as reverse selective bactericidal action in order to distinguish it from the above mentioned normal action.

Certain of the substances which have been power have been used or proposed for use for bactericidal purposes, particularly where a selective bactericidal effect has been desired. Since the time of Ehrlich however the main emphasis in the chemo-therapeutic fieldhas been laid on the improvement of parasitocidal or bactericidal substances by chemical manipulation of the molecule, whereby a specific substance might be produced or obtained having specific or general therapeutic action. In the present invention, however, I have departed from this principle and I have established the principle of supplementary selective bacteriostasis. According to the present invention I accomplish the improvement of bactericidal properties, not by chemicalmanipulation of the molecule, but 'b using a mixture of dyes of opposite se ective capacities, and thus fortif ing the weakness of one by the strength 0 the other, and obtaining a mixture or composition possessing a high degree of extrinsic bacteriostatic capacity for both Gram-positive'and Gram-negative organisms.

I have found that compositions compounded of or containing mixtures of one or more substances having normal selective bactericidal action and one or more substances having reverse bactericidal action are eflicacious found that a solution containing the normal and reverse substances was eflicacious as a germlcide, 1n a strength 1n which the normal or reverse substance actlng alone would be ineffective against certain groups of organisms.

For simplicity I will refer to the substances which exhibit selective bactericidal or-bacteriostatic properties for or toward Gram-positive organisms as Gram-positive substances; and substances which exhibit selective bactericidal or bacteriostatic properties for or toward Gram-negative organisms as Gram-negative substances.

The Gram-positive substances and Gramnegative substances which are compounded in makin the new compositions should be such as do not react with each other 'to neutralize or destro the selective bacteri- .cidal properties. T e Gram-positive substances may for example be triphen lmethane dyes having normal bacterici a1 power, and particularly basic triphenylmethane dyes. Gentian violet, which is a mixture of crystal violet (80 parts) and methyl violet (10 parts) with or without dextrin (10 parts) is a particularly effective Gram-positive substance when used, for example, with a Gram-negative substance such as acrifiavine. Among other Gram-positive substances may be mentioned crystal violet, methyl violet, etc. The Gram-negative substances which I have found of special value in the new compositions are neutral dyes of the acridine series and particularly neutral fiavine dyes such as acriflavine, neutral proflavine, etc. The basic triphenylmethane dyes and the neutral acridine dyes can be compounded without objectionable reaction.

The invention will be further illustrated by the following specific examples but it will be understood that the invention is not limited thereto. The parts are by weight.

10 parts of gentian violet and 10 parts of neutral acriflavine are intimately mixed and dissolved in 2000 parts of boiling water. The solution is allowed to cool and thecool solution is kept as a stock solution in a brown glass container or bottle. The strength (1 to 100) of this stock solutionis usually diluted to a strength of 1 to 500 when the solution is to be.used for example by applying it to the surface of wounds in strength when needed.

the treatment of .granulating surfaces or for saturation of gauze to be packed into the granulated wounds. 7

The dry ingredients may be compounded with each other inthe desired proportions and the resulting composition marketed and used for making a solution of the desired For example, equal parts by weight of the gentian violet and neutral acriflavine may be intimately mixed, and formed into tablets or packaged in capsules, etc. so that a single tablet or capsule contains a definite amount of the composition suitable for making a solution of definite strength when dissolved ina given amount of water. Instead of com ounding the ingredients in a dry state, t ey may be compounded in solution toform a strong or saturated solution of definite content of the ingredients such that it can be diluted with a predetermined amount of water to give a solution of appropriate strength for use.&

The new compositions can be used for various purposes where a practically universal bactericidal effect is desired. They are of special value for the treatment of infection, but can also be used for obtaining substantially bacteria free or sterile results in places or solutions which are desired to be kept free from infection or to make free from bactericidal infection. Industrfal solutions may be treated with the composition and. where the ingredients of the composition may be objectionable in the sterilized product, they may be precipitated and removed therefrom by appropriate chemical treatment. For example, the compositions may be used in sterilizing or preserving sugar solutions and the dyestuffs can be subsequently precipitated by chemical treatment and removed from the solution.

The nature and proportions 'of the ingredients of the composition'can be varied.

In cases where the predominating organism is known to be of a Gram-negative type, an increased amount of the acriflavine can be used, for example, two parts of acrifiavine to one part of gentian violet; while in cases where the predominating organisms are known to be of the Gram-positive type the relative proportions may be reversed, e. g. to two arts of gentian violet and one part of acri avine. The ingredients in the desired proportions may be ground together or mixed in suit-able way and kept either in a dry condition as a powder or in the form of tablets, etc. until wanted for use, or in the form of a concentrated or strong solution. In the above example the gentian violet may be substituted by crystal violet, methyl violet, etc. while neutral profiavine or other flavme dyes may be used in place of acriflavine. The compositions are of more or less general use and can becompounded with other ingredients for nihking.

ointments, salves, etc. for the treatment of cuts, bruises, etc.

Certain substances which are Gram-negative but which are strongly acid in character cannot be used with Gram-positive substances which are basic in character because or the reaction which such acid and basic selective capabilities which can cuts of the composition if used alone in sufficiently strong concentrations, may kill or inhibit substantially all organisms, while it the concentrations are too weak they may be without effect on any of the organisms. Between these two limiting extremes of concentration, however, there exists a considerable range of concentrations of the dyes where the selective effects are obtained. Between these hmits, the Gram-positive substances aflect the Gram-positive organisms, and the Gram-negative substances the Gram-negative organisms. The effective concentrations also depend on the specific organisms; for example, ,a solution ofneutral acriflavine too weak to have any eflect on Gram-positive'spore bearers kills or inhibits most Gram-negative organisms. On the other hand, although mixtures of Grampositive and Gram-negative organisms may not be afiected, or. may be very little affected, when treated with weak concentrations of gentian violet alone or of neutral acriflavine alone, yet when exposed to the action of substantially similar concentrations of a mixture containing both gentian violet and acriflavine-substantially all of the organisms of both groups are killed or in-v superior advantages as germicidal agents on certain Gram-positive non-spore bearers such as for example Staphylococcus aureus, :1. species of bacterla commonly causlng clinical infection. The bactericidal power of the compositions adapts'them for use for. treating fecal matter and of destroying or' retarding growth of bacteria therein.

It will thus be seen that the invention provides a new composition having important advantages and being-of general and practically universal application for bactericidal .or bacteriostatic purposes. It will. further be seen that the invention is a composition comprising substances of opposite selective bactericidal properties of which the action of one supplements and modifies the action/of the other so that the composition itself is of general application where it is de sired to kill or inhibit organisms of various kinds, both Gram-positive and Gram-negative in character. Q

It has been found that it is almost impossible to tell in a given experiment whether the bacteria have been actually killed or simply inhibited. In view of this fact the term kill the micro-organisms or inhibit their growth and also the treatment of uninfected material to prevent infection.

I claim:

1. A germicide composition comprising a substance having a selective bactericidal action against Gram-positive bacteria and a substance having a selective bactericidal action against Gram-negative bacteria, the said substances being capable of being compounded together without objectionable interaction or destruction of the selective bactericidal capacities of the respective substances.

2. A germicide composition comprising a non-acid substance exerting a selective bactericidal action on Gram-positive bacteria and 'a non-acid substance exerting a selective bactericidal action on Gram-negative bacteria which substances can be compounded together without objectionable interaction or destruction of the selective bactericidal capacities of the respective sub- I stances. i

3. A germicide composition comprising a basic t-riphenylmethane dye and a dye which exerts selective bactericidal action against Gram-negative bacteria and which can be compounded with the triphenylmethane-dye without objectionable interaction or destruction of the selective bactericidal capacities of the respective dyes,

4. A germicide composition comprising a basic triphenylmethane dye and a neutral aeridine dye, said composition having a bactericidal or bacteriostatic action on both Gram-positive and Gram-negative bacteria acridine series having a selective action on Gram-lie ative bacteria and which can be compoun ed with gentian violet without objectionableinteraction or destruction of the selective bactericidal capacities of the respective substances.

6. A germicide composition comprising gentian violet and neutral acriflavine. r 7 A geruucide composition comprising gentian violet and neutral acriflavlne in approximately equal proportions.

' '8. A germicide composition comprising a dyestufi' havingY selective bactericidal properties toward ram-positive bacteria and a dyestufi. having selective bactericidal properties toward Gram-negative bacteria, said I In testimony whereof I afiix my signature.

JOHN WQOLMAN' CHURCHMAN. 

